Treatment modalities that effectively control the metastatic progression of prostate cancer (CaP) are not yet available. This is due in part to the differential response of primary and metastatic CaP to chemotherapy. The response of CaP cells to anti-proliferative and anti-metastatic drugs may be modulated through bidirectional inductive interactions between tumor cells and organ specific stromal cells (e.g., fibroblast and endothelial cells). Novel combination therapies that can effectively neutralize the protective effect of these tumor- stroma interactions should significantly enhance the efficacy of conventional chemotherapy. To test these hypotheses, the contribution of organ specific stroma (e.g., bone, lung) in modulating the response of CaP cells to drug-induced cytotoxicity, apoptosis, and multi drug resistance will be investigated, using both CaP and stromal human primary cell cultures. For these studies, established (e.g., doxorubicin, taxol) and novel (e.g., chemically modified tetracyclins, (CMT)) drugs will used. Alterations in the pattern of gene expression, when tumor cells are grown alone, in co- cultures with stromal cells or with stromal extracellular matrix (ECM), will be investigated using a human cDNA expression array system. The expression of gap-junctional proteins and the multi drug resistance phenotype will be correlated to the enhanced resistance of tumor cells to cytotoxic drugs in the presence of stroma (Aim 1). The contribution of tumor-stroma interactions in modulating the production and activity of metastasis promoting factors (e.g., matrix degrading enzymes, their inhibitors and CD44) will be identified (Aim 2). The efficacy of a combination drug treatment strategy that can neutralize the enhanced resistance of CaP cells to cytotoxic drugs will be examined in two models of CaP metastasis (e.g., spontaneous and induced). These models resemble early and late stage CaP in human. The combination treatment will involve the use of two drugs (e.g., taxol/doxorubicin and CMT-3) that have cytotoxic and antimetastatic actions. In addition, some drugs that overcome the enhanced drug resistance of tumor cells, due to the stromal influence, will also be tested in the combination treatment strategy (Aim 3). The results of this proposed study should not only enhance our understanding of the contribution of tumor-stroma interactions in controlling the response of prostate tumor by chemotherapy but would also suggest novel combination therapies that can effectively control the metastatic progression of CaP.